Bibliographical details of various publications referred to in this specification are collected at the end of the description.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Many non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, act by inhibiting cyclooxygenase, which in turn affects production of various prostaglandins including prostaglandin H2 (PGH2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane (TX) A2.
As each prostaglandin has different biological activities, cyclooxygenase inhibition may impact on a number of biological processes with adverse effects. For example, this has been known to include gastric toxicity and cardiovascular complications associated with prostacyclin loss. Consequently, targeting the production of particular prostaglandins downstream of cyclooxygenase provides a much more specific biological effect that avoids such complications.
PGD2 is a major pro-inflammatory mediator of the allergic response and is known to have roles in body temperature regulation, sleep-wake regulation, relaxation of smooth muscle, tactile pain response, bronchoconstriction, and inflammation. It is readily detected in nasal and bronchial lavage fluids of patients with asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis. PGD2 triggers a range of biological effects consistent with a pathological role in asthma and allergy, including airways eosinophilia, obstruction, hypersensitivity and mucus hypersecretion. Compounds that inhibit PGD2 production are therefore attractive targets for drug development.
PGD2 is active in both the central nervous system and peripheral tissues. Production of PGD2 is performed by two genetically distinct PGD2 synthase (PGDS) enzymes: brain-type-PODS (L-PGDS) and haematopoietic-PGDS (H-PGDS). L-PGDS expression in mammals appears to be mostly restricted to the central nervous system, testis and heart. In contrast, PGD2 synthesis in peripheral tissues is likely to be through H-PGDS.
Targeting the inhibition of PGD2 synthesis may allow mediation of pro-inflammatory responses without the side effects of cyclooxygenase inhibition. There is therefore a need for small molecules that inhibit H-PGDS.